3-Phenoxymorphinans and derivatives thereof

ABSTRACT

Levo-rotary 3-phenoxy N-substituted morphinans and derivatives thereof useful as analgesics and/or narcotic antagonists and their preparation form (-)-3-hydroxy-N-lower alkyl morphinan including intermediates in this preparation.

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of U.S. Pat. application Ser.No. 748,022 filed Dec. 6, 1976, now abandoned.

SUMMARY OF THE INVENTION

In accordance with this invention, it has been discovered that compoundsof the formula: ##STR1## wherein R is halo, nitro, lower alkyl, loweralkoxy or hydrogen; R₁ is hydrogen, lower alkyl, lower alkenyl, --CH₂(CH₂)_(p) R₂ and ##STR2## R₂ is heteroaromatic, aromatic or cyclo-loweralkyl; p is an integer from 0 to 3; and n is an integer from 1 to 5 andpharmaceutically acceptable salts thereof are useful as pain killinganalgesics and/or narcotic antagonists.

In accordance with this invention, the compound of formula I can beprepared from a compound of the formula ##STR3## wherein R₁ is as above.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "halogen" includes all four halogens, i.e.,bromine, chlorine, fluorine and iodine with fluorine and bromine beingpreferred. The term "lower alkyl" includes both straight and branchedchain saturated aliphatic hydrocarbon groups containing from 1 to 7carbon atoms, i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, etc., with methyl being preferred. The term "lower alkenyl"designates both straight and branched chain aliphatic hydrocarbon groupscontaining from 2 to 7 carbon atoms which contain one olefinic doublebond such as vinyl, allyl, prop-2-en-1-yl, etc. The preferred loweralkenyl groups are --CH₂ --CH═CH₂, ##STR4##

The term "cyclo-lower alkyl" designates saturated cyclic aliphatichydrocarbon groups containing a ring of from 3 to 6 carbon atoms. Amongthe preferred cyclo-lower alkyl groups are cyclopropyl, cyclobutyl andcyclohexyl. The term "lower alkoxy" designates lower alkoxy groupscontaining from 1 to 7 carbon atoms such as methoxy, ethoxy, propoxy,isopropoxy, etc.

The term "heteroaromatic" designates hydrocarbon ring systems containinga hetero atom selected from the group consisting of oxygen, nitrogen, orsulfur and having 5 or 6 members in the ring structure. Among thepreferred heteroaromatic ring structures are included thienyl, pyrolyl,furyl, pyridyl, pyranyl, etc.

The compound of formula I is prepared from the compound of formula II byreacting the compound of formula II with a compound of the formula##STR5## wherein R and n are as above; and X is halogen. The compoundsof formula II and III are reacted to form the compound of formula Iutilizing a copper catalyst. This reaction is carried out in an organicsolvent in the presence of an inorganic alkali metal base. In carryingout this reaction, any conventional organic solvent can be utilized.Among the preferred solvents are nitrobenzene, collidine, diglime andtertiary amines. Among the tertiary amines are included the cyclictertiary amines such as pyridine and the tri-lower alkyl amines such astrimethyl amine, triethyl amine, etc. This reaction is also carried outin the presence of an inorganic base, such as an alkali metal base.Among the preferred bases are included the alkali metal hydroxides suchas potassium and sodium hydroxide as well as the alkali metal carbonatesand bicarbonates such as sodium carbonate, potassium carbonate, sodiumbicarbonate and potassium bicarbonate. The preferred inorganic base forutilization in this invention is a weak base such as potassiumcarbonate. In carrying out this reaction, temperature and pressure arenot critical and this reaction can be carried out at room temperatureand atmospheric pressure. However, if desired, elevated temperatures canbe utilized. Generally, it is preferred to utilize temperatures of from100°-250° C. in carrying out this reaction. This reaction takes place inthe presence of a copper catalyst such as cupric chloride, cupricbromide, cupric sulfate, cuprous iodide, a mixture of copper-bronze andmetalic copper, with granual copper being preferred.

Where R in the compound of formula I is a hydroxy group, the reaction ofthe compound of formula II with the compound of formula III in theaforementioned manner produces the compound of formula I where R ishydroxy in poor yields. Therefore, it is preferred to prepare thiscompound according to another means. This is accomplished by utilizing acompound of formula I where R is lower alkoxy as a starting material,i.e. a compound of the formula ##STR6## wherein n, R₁ are as above; andR₃ is lower alkyl. By utilizing the compound of formula I-A as astarting material, a compound of the formula: ##STR7## is produced.

The compound of formula I-A is converted to the compound of formula I-Bby ether cleavage. Any conventional method of ether cleavage can beutilized. Among the preferred methods is by treating the compound offormula I-A with potassium hydroxide in diglyme or by treating thecompound of formula I-A with pyriding hydrochloride or aqueous hydrogenbromide in acetic acid. Any of the conditions conventional in ethercleavage can be utilized to convert the compound of formula I-A to I-B.It should be noted that ether cleavage does not cleave the phenoxygroup. Therefore, the phenoxy group cannot be cleaved from the compoundof formula I to produce a material which would be an addicting narcotic.

Where R₁ in the compound of formula I is methyl, i.e. a compound of theformula: ##STR8## where n and R are as above. This compound can beconverted in accordance with another embodiment of this invention to acompound of the formula: ##STR9## wherein R, R₂, p and n are as abovve;or a compound of the formula: ##STR10##

In the conversion of the compound of formula I-C to I-D, the compound offormula I-E is formed as an intermediate. In forming the compound offormula I-E, the compound of formula I-C is reacted with a compound ofthe formula: ##STR11## wherein R₂, p and X are as above. This reactionis carried out by refluxing in the presence of an inert organic solvent.Any conventional aromatic solvent can be used in this reaction. Amongthe preferred are the aromatic hydrocarbon solvents such as benzene ortoluene. If, desired, the compound of formula I-E can be converted tothe compound of formula I-D by treatment with an aluminum hydridereducing agent such as an alkali metal aluminum hydride, i.e. lithiumaluminum hydride or a di(lower alkyl) aluminum hydride such asdiisobutyl aluminum hydride. Any of the conditions conventional inutilizing these aluminum hydride reducing agents can be utilized tocarry out this reduction.

In accordance with another embodiment of this invention, the compound offormula I-D can be prepared from the compound of formula I-C via thefollowing intermediates: ##STR12## wherein R and n are as above##STR13## wherein R and n are as above.

The compound of formula I-C is converted to the compound of formula VIby treating the compound of formula I-C with trichloroethylchloroformate. In carrying out this rection, any inert organic solventcan be utilized as the organic solvent. Among the preferred solvents arethe aromatic hydrocarbon solvents such as benzene, toluene, etc.Generally, this reaction is carried out in the presence of a weak base.Any of the conventional weak inorganic bases can be utilized in thisreaction. Among the preferred weak bases are the alkali metal carbonatesand bicarbonates such as potassium or sodium carbonate. In carrying outthis reaction, temperature and pressure are not critical and thisreaction can be carried out at room temperature or atmospheric pressure.On the other hand, elevated temperatures and pressures can be utilized.Generally, it is preferred to carry out this reaction at the refluxtemperature of the reaction medium.

The compound of formula VI is converted to the compound of formula VIIby treatment with zinc in a lower alkanoic acid. The lower alkanoic acidserves as the solvent medium for this reaction. Any conventional loweralkanoic acids such as acetic acid, propionic acid, etc., can beutilized. In carrying out this reaction, temperature and pressure arenot critical and this reaction can be carried out at room temperatureand atmospheric pressure. On the other hand, temperatures as high as100° C. can be utilized to carry out this reaction.

In accordance with another embodiment of this invention, the compound offormula I-C can be converted to the compound of formula VII via anyprocedure for dialkylation. Any conventional dialkylating agent andprocedure can be utilized to convert the compound of formula I-C to thecompound of formula VII. Among the dialkylating agents which can beutilized in this reaction are included cyanogen bromide followed bytreatment with an inorganic mineral acid or ethyl or phenylchloroformate ester followed by treatment with an alkali metal hydroxidein a lower alkanol. Any of the conditions conventional in utilizingthese di-alkylating agents can be utilized to affect the conversion of acompound of formula I-C to a compound of formula VII. The compound offormula VII can be converted to the compound of formula I-D by reactingthe compound of formula VII with a compound of the formula

    X--CH.sub.2 --(CH.sub.2).sub.p --R.sub.2                   X

where X, R₂ and p are as above.

The compound of the formula VII is reacted with the compound of theformula X to produce the compound of formula I-D in a organic polarsolvent medium utilizing a temperature of from 120° C. to 300° C. Incarrying out this reaction, any polar solvent having a boiling point offrom 120° C. to 300° C. can be utilized. Among the preferred solventsare included the high boiling polar solvents such as dimethyl sulfoxide,dimethyl formamide. This reaction is carried out in the presence of aninorganic alkali metal base. Any conventional inorganic alkali metalbase, such as sodium bicarbonate, potassium carbonate, sodium carbonatecan be utilized in this reaction. Generally, it is preferred to utilizeweak organic bases such as sodium or potassium bicarbonate or carbonate.In carrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature or atmosphericpressure. Generally, it is preferred to carry out this reaction underreflux conditions.

In accordance with another embodiment of this invention, the compound offormula VII is converted to the compound of formula I-E by reaction witha compound of formula IV. This reaction is carried out in an inert polarorganic solvent. Any conventional polar solvent can be utilized. Amongthe preferred organic polar solvents are included benzene, toluene,methylene chloride. This reaction is carried in the presence of anorganic base such as triethylamine, pyridine and the like. In carryingout this reaction, temperature and pressure are not critical and thereaction can be carried out at room temperature or elevatedtemperatures.

In accordance with another embodiment of the invention, the compound offormula VII can be converted to a compound of the formula ##STR14##wherein R and n are as above; and R₇ is lower alkyl, or lower alkenyl byreaction with a compound of the formula

    X--R.sub.7

where X and R₇ are as above. This reaction is carried out by the sameprocedure as described in connection with the reaction of a compound VIIwith a compound of the formula X to produce a compound of the formulaI-D.

In accordance with another embodiment of this invention, the compound offormula I can be prepared from a compound of the formula ##STR15##wherein R₁ is as above and R₉ is lower alkyl via the followingintermediates ##STR16## wherein R, R₁ and n are as above.

In converting the compound of formula XI to the compound of formula XII,ether cleavage is utilized. Any conventional method of ether cleavagecan be utilized to carry out this conversion. Among the preferredmethods is to treat the compound of formula XI with alkali metalhydroxides such as sodium or potassium hydroxide in an ether solventsuch as diglime. Generally, this reaction is carried out at the refluxtemperature of the reaction medium. The compound of formula XII isconverted to the compound of formula XIII by reacting the compound offormula XII with a compound of formula III. This reaction is carried outin the same manner as described in connection with the reaction of thecompound of formula II with a compound of formula III to produce thecompound of formula I.

The compound of formula XIII is converted to the compound of formula Iby cyclization. This cyclization is carried out by treating the compoundof formula XIII with a strong mineral acid. Any conventional strongmineral acid can be utilized such as phosphoric acid, sulfuric acid,hydrochloric acid, with phosphoric acid being preferred. The inorganicacid can be utilized as the solvent medium. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature and atmospheric pressure. On theother hand, temperatures as high as 250° C. can be utilized. Generally,it is preferred to carry out this reaction with a temperature of from100°-200° C.

The compounds of formula I above form pharmaceutically acceptable acidaddition salts with inorganic acids. Thus, the compounds of the presentinvention form pharmaceutically acceptable acid addition salts withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid and phosphoric acid; and with organic acids such as tartaric acid,oxalic acid, citric acid, camphorsulfonic acid, ethanesulfonic acid,toluenesulfonic acid, salicylic acid, ascorbic acid, maleic acid,succinic acid, formic acid, acetic acid and the like.

The compounds of formula I and their pharmaceutically acceptable saltsare useful as analgesics and/or as narcotic antagonists. Thesecompounds, when administered orally or parentally, provide a relief frompain in the same manner as codeine. Furthermore, the compounds of thisinvention cannot be degraded chemically into compounds which haveaddiction liability such as dromoran.

The compounds of formula I and salts as herein described can beincorporated into standard pharmaceutical dosage forms, for example,they are useful for oral or parenteral application with the usualpharmaceutical adjuvant material, for example, organic or inorganicinert carrier materials such as water, gelatin, lactose, starch,magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols andthe like. The pharmaceutical preparations can be employed in a solidform, for example, as tablets, suppositories, capsules, or in liquidform, for example, as solutions, suspensions or emulsions.Pharmaceutical adjuvant materials can be added and includepreservatives, stabilizers, wetting or emulsifying agents, salts tochange the osmotic pressure or to act as buffers. The pharmaceuticalpreparations can also contain other therapeutically active substances.

The daily dose administered for the compounds will of course vary withthe particular novel compounds employed because of the very potency ofthe compounds, the chosen route of administration and the size of therecipient. The dosage administered is not subject to definite bounds butit will usually be in effective amounts of the pharmacological functionof the compound of formula I. Representative of a typical method foradministering the compounds of formula I is by the oral typeadministration route. By this route, a tablet containing the compound offormula I can be administered orally at the rate of 0.01 microgram to0.15 microgram per day per kilogram of body weight.

The compounds of formula I above and their salts are used as analgesicpain killing agents. This analgesic activity can be demonstrated in thestandard phenylquinone writhing test (Sigmund et al., Proc. Soc. Exp.Biol. Med. 95: 729 [1957]). The compounds of this inventionsignificantly reduce pain and produce analgesic effects in mice exposedto intra-abdominally induced chemical pain. The ED₅₀ was the dose whichreduced the total number of writhes by 50%. When the following compoundsof formula I are utilized as the test substances, analgesic activity isobserved as shown by the following ED₅₀ levels when compared to thestandard analgesic agent codeine:

(--)-3-phenoxy-N-methylmorphinan tartrate--ED₅₀ 2.0 mg/kg (S.C.);

(--)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride--ED₅₀ 23 mg/kg(s.c.);

.[.(--)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride--ED₅₀ 2.0mg/kg (s.c.);.].

.[.(--)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride--ED₅₀ 13.0mg/kg (s.c.);.].

.[.(--)-3-phenoxy-N-phenethylmorphinan oxalate--ED₅₀ 0.9 mg/kg(s.c.);.].

.[.(--)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan oxalate--ED₅₀ 1.0 mg/kg(s.c.);.].

.[.(--)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinan sulfate--ED₅₀ 13.0mg/kg (s.c.);.].

.[.(--)-3-(m-fluoro)phenoxy-N-methylmorphinan d-tartrate--ED₅₀ 6.0 mg/kg(s.c.);.].

.[.(--)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinanhydrochloride--ED₅₀ 2.5 mg/kg (s.c.);.].

.[.(--)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinanhydrochloride--ED₅₀ 1.3 mg/kg (s.c.);.].

(--)-3-(m-Methoxy)phenoxy-N-methylmorphinan oxalate--ED₅₀ 2.5 mg/kg(s.c.).

(--)-3-(o-Methoxy)phenoxy-N-methylmorphinan oxalate--ED₅₀ 0.49 mg/kg(s.c.).

(--)-3-(p-Hydroxy)phenoxy-N-methylmorphinan hydrochloride--ED₅₀ 1.3mg/kg (s.c.).

(--)-3-(m-Hydroxy)phenoxy-N-methylmorphinan d-tartrate--ED₅₀ 9.0 mg/kg(s.c.).

(--)-3-(o-Hydroxy)phenoxy-N-methylmorphinan d-tartrate--ED₅₀ 1.8 mg/kg(s.c.).

(--)-3-(o-Nitro)phenoxy-N-methylmorphinan hydrochloride--ED₅₀ 2.8 mg/kg(s.c.).

(--)-3-(p-Fluoro)phenoxy-N-methylmorphinan hydrochloride--ED₅₀ 1.0 mg/kg(s.c.).

(--)-3-(o-Fluoro)phenoxy-N-methylmorphinan oxalate--ED₅₀ 3.0 mg/kg(s.c.).

(--)-3-Pentafluorophenoxy-N-methylmorphinan oxalate--ED₅₀ 9.2 mg/kg(s.c.).

(--)-3-Phenoxy-N-cyclopropylmethylmorphinan hydrochloride(17)--ED₅₀ 1.7mg/kg (s.c.). and

Codeine--ED₅₀ 3.9 mg/kg (s.c.).

The compounds of formulae I above effectively counteract morphineanalgesia. This activity can be demonstrated in the mice tail flick testfor morphine antagonism. This test is used to measure narcoticantagonism. Compounds are given subcutaneously 10 minutes prior tomorphine sulfate. The percent evaluation in reaction time was determinedduring each test for 10 mg/kg s.c. of morphine sulfate and actualpercent increase was used in calculating the percent antagonism ofmorphine analgesia. The percent antagonism was calculated according tothe formula of Harris and Pierson, J. Pharmacol. Exp. Ther., 143:141,1964. When the following representative compound of the presentinvention was utilized as the test substance, morphine antagonismactivity is obtained as shown by the following ED₅₀ level(--)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride

    ED.sub.50 40.28 mg/kg (s.c.).

The term aromatic designates a hydrocarbon aromatic substituent such asphenyl, naphthyl with phenyl being preferred.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees Centigrade. The etherutilized is diethyl ether. Millimeters (mm) as used in the examples ismmHg of mercury.

EXAMPLE 1 (--)-3-Pentafluorophenoxy-N-methylmorphinan

A mixture of 6.0 g (0.023 mol) of (--)-3-hydroxy-N-methylmorphinan, 60ml of freshly distilled pyridine, 4.8 g of potassium carbonate, 9.0 g ofhexafluorobenzene, and 6.0 g of copper (granular) were heated in astainless steel container at 120° C. for 7 days. After cooling, thecontainer was opened and the mixture was filtered. The filtrate wasconcentrated under reduced pressure, and the residue was partitionedbetween ether (700 ml) and 5 N aqueous sodium hydroxide. After removalof ether, the residue was extracted with hexane (200 ml). The residueobtained from the hexane extract (5.0 g) was chromatographed overneutral alumina (75 g), eluted with methylene chloride, diethyl ether,and ethyl acetate. After the fractions were combined, the solvents wereremoved under reduced pressure to give 3.6 g (36%) of crude(--)-3-pentafluorophenoxy-N-methylmorphinan. For analysis, a sample ofthis compound was distilled, bp 150°-160°/0.1 mm, [α]²⁵ D-39.69° (c1.21, MeOH).

To the above base, 3.6 g (0.01 mol) in 20 ml of diethyl ether, asolution of 0.8 g of oxalic acid in 20 ml of ether was added. The crudeoxalate was recrystallized from ethyl acetate to give 3.2 g (73%) of(--)-3-pentafluorophenoxy-N-methylmorphinan oxalate hemihydrate, m.p.157°-160°, [α]²⁵ D-24.50° (c 1.00, MeOH).

EXAMPLE 2 (--)-3-Phenoxy-N-methylmorphinan

A solution of 10.2 g (0.04 mol) of (--)-3-hydroxy-N-methylmorphinan in240 ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 18.5 g of bromobenzene, 13.8 g of potassium carbonate and13.0 g of copper (granular) for 8 days. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspartition between ether (500 ml) and 5 N aqueous sodium hydroxide (200ml). The ether solution was washed with water and dried. After removalof ether, the residue was distilled, bp 180°-185°/0.1 mmHg to give 10.0g (76%) of the base, i.e. (--)-3-phenoxy-N-methylmorphinan. A sample ofthis compound was recrystallized from ether, mp 87°-88°, [α]²⁵ D-60.10°(c 1.01, MeOH).

To the above base, 10.0 g (0.03 mol) in 50 ml of ether, a solution of3.2 g of oxalic acid in 100 ml of ether was added. The crude oxalate wasrecrystallized from ethanol to give 11.5 g (91%) of(--)-3-phenoxy-N-methylmorphinan oxalate, mp 184°-185° (d), [α]²⁵D-35.47° (c 1.00, MeOH).

To 7.0 g (0.02 mol) of base, in 25 ml of acetone with stirring, a warmsolution of 3.5 g of d-tartaric acid in 75 ml of acetone was added. Themixture was stirred at room temperature for 0.5 hr, then at 0° to 5° for4 hrs. The tartrate salt was separated by filtration and recrystallizedfrom ethanol (40 ml) to give 10.0 g (98%) of pure(--)-3-phenoxy-N-methylmorphinan d-tartrate, mp 131°-133°, [α]²⁵D-20.08° (c 0.99, MeOH).

EXAMPLE 3 (--)-3-(p-Methyl)phenoxy-N-methylmorphinan

A solution of 5.0 g (0.019/0.15 mol) (--)-3-hydroxy-N-methylmorphinan in20 ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 6.4 g of p-bromotoluene, 4.0 g of potassium carbonate, and0.2 g of copper (granular) for 9 days. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasextracted with ether (200 ml) and the ether solution was washed with 2 Nsodium hydroxide (100 ml), then water and dried. After removal of ether,the residue was distilled, bp 125°-140° 10.15 mmHg to give 3.9 g (58%)of (--)-3-(p-methyl)phenoxy-N-methylmorphinan. A sample of this compoundwas crystallized from ether, mp 94°-96°, [α]²⁵ D-55.98° (c 1.00, MeOH).

The above base, 3.3 g (0.01 mol), on treatment with hydrogen chloride(anhydrous) in ethyl acetate (5 ml), afforded 3.3 g of crudehydrochloride. Recrystallization from ethyl acetate gave 3.0 g (82%) of(--)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride, mp 223°-224°,[α]²⁵ D-37.85° (c 0.69, MeOH).

EXAMPLE 4 (--)-3-(p-Methoxy)phenoxy-N-methylmorphinan

A solution of 5.1 g (0.02 mol) of (--)-3-hydroxy-N-methylmorphinan in 20ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 7.5 g of p-bromoanisole, 4.01 g of potassium carbonate and0.2 g of copper (granular) for 7 days. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspartitioned between ether (400 ml) and 10 N sodium hydroxide (100 ml).The ether solution was washed with water and dried. After removal ofether, the residue was distilled, bp 139°-155°/0.15 mmHg to give 3.9 g(54%) of the product (--)-3-(p-methoxy)phenoxy-N-methylmorphinan. Thiscompound was crystallized from ether to afford 3.3 g (46%) of pureproduct, mp 130°-132°, [α]²⁵ D-51.59° (c 0.99, MeOH).

The above product, 2.0 g (0.006 mol) on treatment with hydrogen chloride(anhydrous) in ethyl acetate, afforded the crude hydrochloride salt ofthe product, which after crystallization from ethyl acetate gave 1.1 g(50%) of (--)-3-(p-methoxy)-phenoxy-N-methylmorphinan hydrochloride, mp170°-172°, [α]²⁵ D-34.22° (c 0.99, MeOH).

EXAMPLE 5 (--)-3-(m-Methoxy)phenoxy-N-methylmorphinan

A solution of 5.1 g (0.02 mol) of (--)-3-hydroxy-N-methylmorphinan in 20ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 7.5 g of m-bromoanisole, 4.1 g of potassium carbonate and0.2 g of copper (granual) for 10 days. To the reaction mixture was addedether (twice the volume) and filtered. The filtrate was concentratedunder reduced pressure and the residue was partitioned between ether and5 N sodium hydroxide. The ether solution was washed with water anddried. After removal of ether, the residue was distilled, bp145°-160°/0.1 mmHg to give 5.47 g (76%) of the product(--)-3-(m-methoxy)phenoxy-N-methylmorphinan. For analysis, a sample ofthis compound was crystallized from ether, mp. 88°-90°, [α]²⁵ D-61.81°(c 1.00, MeOH).

To the above product, 1.5 g (0.004 mol), in ether, a solution of 0.4 gof oxalic acid in ether was added. The crude oxalate salt wasrecrystallized from ethanol-ether to give 1.7 g (91%) of(--)-3-(m-methoxy)phenoxy-N-methylmorphinan oxalate, mp 148°-150°, [α]²⁵D-39.60° (c 1.00, MeOH).

EXAMPLE 6 (--)-3-(o-Methoxy)phenoxy-N-methylmorphinan

A solution of 5.1 g (0.02 mol) of (--)-3-hydroxy-N-methylmorphinan in 20ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 7.5 g of o-bromoanisole, 4.1 g of potassium carbonate and5.0 g of copper (granual) for 3 days. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspartitioned between ether and 5 N sodium hydroxide. The ether solutionwas washed with water and dried. After removal of the solvent, theresidue was distilled, bp 165°/0.2 mmHg to give 2.7 g (36%) of theproduct (--)-3-(o-methoxy)phenoxy-N-methylmorphinan. For analysis, asample of this compound was crystallized from ethyl acetate, mp 87°-89°,[α]²⁵ D-59.32° (c 1.16, MeOH).

To the above product, 2.7 g (0.01 mol), in ether a solution of 0.7 g ofoxalic acid in ether was added. The crude oxalate salt wasrecrystallized from ethanol-ether to give 1.8 g (54%) of(--)-3-(o-methoxy)phenoxy-N-methylmorphinan oxalate, mp 185°-187° (d),[α]²⁵ D--37.19° (c 0.99, MeOH).

EXAMPLE 7 (--)-3-(p-Hydroxy)phenoxy-N-methylmorphinan

A mixture of 2.0 g (0.005 mol) of(--)-3-(p-methoxy)phenoxy-N-methylmorphinan and 20 g of pyridinehydrochloride was heated at 220° with stirring under nitrogen for 25minutes, cooled in an ice bath, and diluted with water (50 ml). Themixture was made basic with conc. ammonium hydroxide and extracted withchloroform (100 ml). The chloroform solution was washed with water (50ml) and dried. Removal of the solvent in vacuo gave a residue which wastreated with ether and filtered to give 1.79 g (66%) of the product(--)-3-(p-hydroxy)phenoxy-N-methylmorphinan. For analysis, a sample ofthis compound was crystallized from ethanol-ether, mp 188°-190°, [α]²⁵D-51.6° (c 0.86, MeOH).

The above product, 1.4 g (0.004 mol) on treatment with hydrogen chloride(anhydrous) in ethyl acetate (10 ml), afforded the crude hydrochloride.Crystallization of this compound from ethanol-ethyl acetate gave 1.2 g(78%) of (--)-3-(p-hydroxy)phenoxy-N-methylmorphinan hydrochloride, mp160°-163° (d), [α]²⁵ D-34.55° (c 0.99, MeOH).

EXAMPLE 8 (--)-3-(m-Hydroxy)phenoxy-N-methylmorphinan

A mixture of 3.8 g (0.01 mol) of(--)-3-(m-methoxy)phenoxy-N-methylmorphinan and 30 g of pyridinehydrochloride was heated at 220° with stirring under nitrogen for 25minutes, cooled in an ice bath and diluted with water. The mixture wasmade basic with conc. ammonium hydroxide and extracted with ether. Theether extracts were washed with water and dried. Removal of the solventin vacuo gave 3.2 g (88%) of the product(--)-3-(m-hydroxy)phenoxy-N-methylmorphinan. For analysis, a sample ofthis compound was recrystallized from ethanol, mp 212°-214°, [α]²⁵D-53.13° (c 1.00, MeOH).

To the above product 2.2 g (0.01 mole), in ethanol, a solution of 1.0 gof di-tartaric acid in ethanol (20 ml) was added. The solution wasdiluted with ether and the crystals were collected. The crude salt wasrecrystallized from ethanol-ethyl acetate to give 2.8 g (81%) of(--)-3-(m-hydroxy)phenoxy-N-methylmorphinan d-tartrate ethanolate, mp135°-138°, [α]²⁵ D-19.21° (c 1.26, MeOH).

EXAMPLE 9 (--)-3-(o-Hydroxy)phenoxy-N-methylmorphinan

A mixture of 2.5 g (0.007 mol) of(--)-3-(o-methoxy)phenoxy-N-methylmorphinan and 25.0 g of pyridinehydrochloride was heated at 220° with stirring under nitrogen for 25minutes, cooled in an ice bath and diluted with water (50 ml). Themixture was made basic with conc. aqueous ammonium hydroxide andextracted with chloroform (80 ml). The chloroform solution was washedwith water and dried. Removal of the solvent in vacuo gave the crudebase, which after crystallization from ethyl acetate-hexane afforded 1.5g (63%) of pure product (--)-3-(o-hydroxy)-phenoxy-N-methylmorphinan, mp167°-168°, [α]²⁵ D-52.91° (c 1.07, MeOH).

The above product, 0.152 g (0.001 mol) and 0.07 g of d-tartaric acidwere dissolved in 1 ml of hot ethanol and allowed to crystallize at roomtemperature. The crude salt was recrystallized from ethanol to give0.222 g (94%) of (--)-3-(o-hydroxy)phenoxy-N-methylmorphinan d-tartrateethanolate, mp 111°-112°, [α]²⁵ D-15.96° (c 1.07, MeOH).

EXAMPLE 10 (--)-3-(o-Nitro)phenoxy-N-methylmorphinan

A solution of 6.4 g (0.02 mol) of (--)-3-hydroxy-N-methylmorphinan in 30ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 10.0 g of 1-bromo-2-nitrobenzene, 6.0 g of potassiumcarbonate and 0.3 g of copper (granual) for 3 days. The mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was partitioned between ether and 5 N sodium hydroxide. Theether solution was washed with water and dried. The ether was removedand the residue was partitioned again between chloroform and 5 N sodiumhydroxide. After removal of chloroform in vacuo, the residue wascrystallized from ether to give 2.1 g (22%) of the product(--)-3-(o-nitro)phenoxy-N-methylmorphinan, mp 158°-160°, [α]²⁵ D-53.16°(c 0.99, MeOH).

The above product, 2.0 g (0.005 mol), on treatment with hydrogenchloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride,which after crystallization from ethyl acetate gave 1.2 g (54%) of(--)-3-(o-nitro)phenoxy-N-methylmorphinan hydrochloride hemihydrate, mp155°-157° (d), [α]²⁵ D-32.62° (c 0.99, MeOH).

EXAMPLE 11 (--)-3-(p-Fluoro)phenoxy-N-methylmorphinan

A solution of 5.1 g (0.02 mol) of (--)-3-hydroxy-N-methylmorphinan in 20ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 17.0 g of p-fluoro-bromobenzene, 4.1 g of potassiumcarbonate and 0.2 g of copper (granual) for 5 days. To the reactionmixture, ether (twice the volume) was added and filtered. The filtratewas concentrated in vacuo, and the residue was suspended in 150 ml ofhot hexane and filtered. The filtrate was washed with 5 N sodiumhydroxide then water and dried. After removal of the solvent, theresidue was crystallized from hexane to give 4.5 g (65%) of the product(--)-3-(p-fluoro)phenoxy-N-methylmorphinan, mp 102°-104°, [α]²⁵ D-53.36°(c 1.00, MeOH).

The above product, 4.0 g (0.01 mol), on treatment with hydrogen chloride(anhydrous) in ethyl acetate, afforded the crude hydrochloride.Recrystallization from ethyl acetate gave 4.0 g (89%) of(--)-3-(p-fluoro)phenoxy-N-methylmorphinan hydrochloride hemihydrate, mp162°-164°, [α]²⁵ D-34.83° (c 0.98, MeOH).

EXAMPLE 12 (--)-3-(o-Fluoro)phenoxy-N-methylmorphinan

A solution of 2.0 g (0.007 mol) of (--)-3-hydroxy-N-methylmorphinan in10 ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 3.5 g of o-fluorobromobenzene, 2.0 g of potassiumcarbonate and 2.0 g of copper (granual) for 2 days. To the reactionmixture, ether (twice the volume) was added and filtered. The filtratewas concentrated in vacuo and the residue was taken up in ether (200 ml)and washed with 5 N sodium hydroxide. The ether solution was washed withwater and dried. Removal of ether gave 2.5 g (92%) of crude product(--)-3-(o-fluoro)phenoxy-N-methylmorphinan. For analysis, a sample ofthis compound was crystallized from ether, mp 113°-115°, [α]²⁵ D-48.67°(c 0.95, MeOH).

To the above product 2.5 g (0.007 mol), in ether a solution of 0.7 goxalic acid in ether (25 ml) was added. The crude oxalate salt wasrecrystallized from ethanol to give 2.4 g (77%) of(--)-3-(o-fluoro)phenoxy-N-methylmorphinan oxalate, mp 180°-182°, [α]²⁵D-30.98° (c 1.00, MeOH).

EXAMPLE 13 (--)-3-Phenoxy-N-trichlorocarbethoxymorphinan

To a mixture of 2.3 g (0.007 mol) of (--)-3-phenoxy-N-methylmorphinan,150 ml of benzene and 0.35 g of potassium carbonate was added dropwise,3.3 g of 2,2,2-trichloroethyl chloroformate. The reaction mixture wasstirred at reflux for 6 days. The mixture was diluted with ether andextracted with 4 N hydrochloride acid. The organic phase was washed withdilute ammonium hydroxide, water, and dried. Removal of solvent gave 3.4g (99%) of the product (--)-3-phenoxy-N-trichlorocarbethoxymorphinan.For analysis, a sample of this compound was distilled, bp 230°-240°/0.05mmHg, [α]²⁵ D-119.65° (c 0.95, MeOH).

EXAMPLE 14 (--)-3-Phenoxymorphinan

To a solution of 3.4 g (0.007 mol) of(--)-3-phenoxy-N-trichlorocarbethoxymorphinan in 40 ml of 90% aceticacid was added portionwise 2.0 g of zinc-dust. The mixture was stirredat room temperature for 16 hours and filtered. The filtrate wasconcentrated in vacuo and the residue was partitioned between ether anddilute ammonium hydroxide. The ether solution was extracted with 4 Nhydrochloric acid. The acidic solution was extracted with chloroform.After removal of chloroform, the crude hydrochloride was crystallizedfrom ethanol to afford 0.7 g (29%) of (--)-3-phenoxymorphinanhydrochloride, mp 322°-324°, [α]²⁵ D-33.88° (c 1.00, MeOH).

EXAMPLE 15 (--)-3-Phenoxy-17-cyclopropylcarbonylmorphinan

To a solution of 3.7 g (0.011 mol) of (--)-3-phenoxy-N-methylmorphinanin 50 ml of toluene, 5.8 g of cyclopropane carboxylic acid chloride in25 ml of toluene was added dropwise at 5°. The mixture was allowed towarm to room temperature and was then refluxed for 15 hours. The solventwas removed in vacuo and the residue partitioned between ether anddilute hydrochloric acid. The ether solution was washed with water anddried. Removal of the solvent in vacuo afforded 4.2 g (99%) of(--)-3-phenoxy-N-cyclopropylcarbonylmorphinan. For analysis, a sample ofthis compound was distilled, bp 230°-240°/0.05 mmHg, [α]²⁵ D-173.45° (c0.99, MeOH).

EXAMPLE 16 (--)-3-Phenoxy-N-cyclopropylmethylmorphinan

To a suspension of 0.4 g of lithium aluminum hydride in 20 ml ofanhydrous tetrahydrofuran was added dropwise, 4.6 g (0.011 mol) of(--)-3-phenoxy-N-cyclopropylcarbonylmorphinan in 30 ml of anhydroustetrahydrofuran over a period of 15 minutes. After the mixture had beenrefluxed under nitrogen for 16 hours, it was cooled to room temperatureand water was added dropwise. The resulting suspension was filtered andthe filtrate was concentrated. The residue was partitioned between etherand 4 N hydrochloric acid. The acidic phase was made basic withconcentrated ammonium hydroxide and the aqueous suspension was extractedwith ether. The ether solution was washed with water and dried. Removalof the ether under reduced pressure afforded 2.6 g (59%) of the product(--)-3-phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample ofthis compound was distilled, bp 190°200°/0.1 mmHg, [α]²⁵ D-89.07° (c0.99, MeOH).

The above product, 2.6 g (0.007 mol), on treatment with hydrogenchloride (anhydrous) in ether afforded the crude hydrochloride, whichafter crystallization from ethyl acetate gave 1.4 g (50%) of(--)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride, mp 186°-188°,[α]²⁵ D-67.16° (c 1.00, MeOH).

EXAMPLE 17(--)-1-(p-Hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline

A mixture of 253.9 g (0.935 mol) of(--)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinolineand 1.2 l. of diethylene glycol was warmed to 80°-100° and 260 g ofpotassium hydroxide (85 % A.C.S. grade) was added. The reaction mixturewas heated to 210° and stirred at this temperature under a constantstream of nitrogen for 36 hours. During this period, time to time thestop cock was removed to allow escape of water vapor. If this is notdone, the desired inner temperature of 210° cannot be attained. The darkbrown solution was cooled to room temperature and diluted with water(600 ml) and extracted with ether (400 ml). The aqueous solution wasmade acidic with concentrated aqueous hydrochloric acid and thenbasified with concentrated aqueous ammonium hydroxide. The aqueoussuspension was extracted with ethyl acetate (4×250 ml). The ethylacetate solution was washed with water and dried. Removal of the solventgave 172.5 g (72%) of crude(--)-1-(p-hydroxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline.For analysis, a sample of this compound was recrystallized fromtetrahydrofuran-heptane, mp 119°-120°, [α]²⁵ D-36.01° (c 0.98, MeOH).

EXAMPLE 18(--)-1-(p-Phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline

A solution of 2.4 g (0.009 mol) of(--)-1-(p-hydroxybenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline,10 ml of freshly distilled pyridine was refluxed with stirring undernitrogen with 3.1 g of bromobenzene, 2.0 g of potassium carbonate, and0.1 g of copper (granual) for 9 days. The mixture was filtered and thefiltrate was concentrated under reduced pressure. To the residue, ether(150 ml) was added and the ether insoluble material was removed byfiltration. The filtrate was extracted with 2 N sodium hydroxide, washedwith water, and dried. Removal of the solvent gave 1.18 g (38%) of theproduct(--)-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline(20). For analysis, a sample of this compound was distilled, bp120°/0.15 mmHg, [α]²⁵ D-18.53° (c 1.14, MeOH).

To the above product, 1.0 g (0.003 mol), in 5 ml of ether, a solution of0.3 g of oxalic acid in ether was added. The crude oxalate wasrecrystallized from ethanol to give 0.581 g (46%) of(--)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinolineoxalate, mp 160°-162°, [α]²⁵ D-37.17° (c 1.00, MeOH).

EXAMPLE 19 Acid catalyzed cyclization of(--)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline

A mixture of 0.5 g. (0.002 mol) of(--)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinolineand 5 ml. of 99% phosphoric acid was heated at 135° with stirring undernitrogen for 3 days. The reaction mixture was pored onto ice-water andmade basic with concentrated ammonium hydroxide. The aqueous suspensionwas extracted with chloroform. The combined chloroform extracts werewashed with water, dried and removal of the solent gave 0.15 g. (30%) ofcrude (--)-3-phenoxy-N-methylmorphinan.

EXAMPLE 20 (--)-3-Phenoxy-N-cyclobutylcarbonylmorphinan

To a solution of 3.9 g. (0.011 mol) of (--)-3-phenoxy-N-methylmorphinanin 50 ml. of toluene 6.9 g. of cyclobutane carboxylic acid chloride in30 ml. of toluene was added dropwise at room temperature. The mixturewas stirred at this temperature for 1 hour, followed by heating atreflux for 12 days. The reaction mixture was cooled to room temperatureand washed successively with 4 N hydrochloric acid, water and 5 N sodiumhydroxide. The organic phase was dried and filtered. Removal of thesolvent in vacuo afforded 2.3 g. (49%) of(--)-3-phenoxy-N-cyclobutylcarbonylmorphinan. For analysis, a sample ofthis compound was distilled, b.p. 220° (0.1 mmHg), [α]_(D) ²⁵ =-163.25°(c 0.98, MeOH).

EXAMPLE 21 (--)-3-Phenoxy-N-cyclobutylmethylmorphinan

To a suspension of 0.4 g. of lithium aluminum hydride in 40 ml. ofanhydrous tetrahydrofuran was added dropwise, 2.1 g. (0.005 mol) of(--)-3-phenoxy-N-cyclobutylcarbonylmorphinan in 20 ml. of anhydroustetrahydrofuran. After the mixture had been refluxed under nitrogen for3 hours, it was cooled to room temperature and water was added dropwise.The resulting suspension was filtered and the filtrate was concentrated.The residue was dissolved in ether (50 ml.) and extracted with 4 Nhydrochloric acid (75 ml.). The aqueous solution was basified with 10 Nsodium hydroxide and extracted with ether (75 ml.). The etherealsolution was washed with water and dried. Removal of the solvent invacuo gave 1.2 g. (59%) of crude base(--)-3-phenoxy-N-cyclobutylmethylmorphinan. For analysis, a sample ofthis compound was distilled, b.p. 215°-225° (0.5 mmHg), [α]_(D) ²⁵=-73.25° (c 0.99, MeOH).

The above base, 1.1 g. (0.003 mol), on treatment with hydrogen chloride(anhydrous) in ethyl acetate, afforded the crude hydrochloride whichafter crystallization from ethyl acetate gave 1.2 g. (100%) of pure(--)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride, m.p.175°-177°, [α]_(D) ²⁵ =-66.59° (c 1.03, MeOH).

EXAMPLE 22 (--)-3-Phenoxy-N-phenylacetylmorphinan

To a mixture of 4.0 g. (0.012 mol) of (--)-3-phenoxymorphinan, 2.5 g. oftriethylamine and 15 ml. of methylene chloride was added dropwise asolution of 2.9 g. of phenyl acetyl chloride in 15 ml. of methylenechloride. After the mixture had been refluxed for 14 hours, it wascooled to room temperature and washed successively with water, 4 Nhydrochloric acid, 2 N sodium hydroxide and water. The organic solutionwas dried and the solvent was evaporated to give 4.4 g. (80%) of thecrude base (--)-3-phenoxy-N-phenylacetylmorphinan. For analysis, asample of this compound was distilled, b.p. 240°-250° (0.05 mmHg),[α]_(D) ²⁵ =133.27° (c 1.11, MeOH).

EXAMPLE 23 (--)-3-Phenoxy-N-phenethylmorphinan

To a suspension of 0.8 g. of lithium aluminum hydride in 40 ml. ofanhydrous tetrahydrofuran was added dropwise, 4.2 g. (0.01 mol) of(--)-3-phenoxy-N-phenylacetylmorphinan in 40 ml. of anhydroustetrahydrofuran over a period of 45 minutes. After the mixture had beenrefluxed under nitrogen for 3 hours, it was cooled to room temperatureand water was added dropwise. The resulting suspension was filtered andthe filtrate was concentrated. The residue was partitioned between etherand water. The ethereal solution was dried and the solvent wasevaporated to give 3.5 g. (86%) of the crude base(--)-3-phenoxy-N-phenethylmorphinan. For analysis, a sample of thiscompound was distilled, b.p. 160°-165° (0.1 mmHg), [α]_(D) ²⁵ =-100.27°(c 0.55, MeOH).

To the above base, 3.2 g. (0.007 mol) in ether, a solution of 0.8 g. ofoxalic acid in ether was added. The crude oxalate was recrystallizedtwice from ethanol to give 1.7 g. (39%) pure(--)-3-phenoxy-N-phenethylmorphinan oxalate, m.p. 217°-219°, [α]_(D) ²⁵=-72.17° (c 1.06, MeOH).

EXAMPLE 24 (--)-3-Phenoxy-N-[(2-furylmethyl)carbonyl]morphinan

To a mixture of 4.0 g. (0.012 mol) of (--)-3-phenoxymorphinan,2.5 g. oftriethylamine and 15 ml. of methylene chloride was added dropwise asolution of 2.7 g. of 2-furyl acetyl chloride. After the mixture hadbeen refluxed for 14 hours, it was cooled to room temperature, andwashed successively with water, 4 N hydrochloric acid, 5 N sodiumhydroxide and water. The organic solution was dried and the solvent wasevaporated to give 5.2 g. (97%) of crude(--)-3-phenoxy-N-[(2-furylmethyl)carbonyl]-morphinan. For analysis, asample of this compound was distilled, b.p. 215°-225° (0.1 mmHg),[α]_(D) ²⁵ =-135.36° (c 1.06, MeOH).

EXAMPLE 25 (--)-3-Phenoxy-N-[2-(2-furyl)ethyl]morphinan

To a suspension of 0.8 g. of lithium aluminum hydride in 40 ml. ofanhydrous tetrahydrofuran was added dropwise, 5.1 g. (0.012 mol) of(--)-3-phenoxy-N-[(2-furylmethyl)carbonyl]morphinan in 40 ml. ofanhydrous tetrahydrofuran. After the mixture had been refluxed undernitrogen for 3 hours, it was cooled to room temperature and water wasadded dropwise. The resulting suspension was filtered and the filtratewas concentrated. The residue was partitioned between ether and water.The ethereal solution was washed with 5 N sodium hydroxide and dried.Removal of the solvent in vacuo gave an oily residue (2.8 g.). Theresidue was purified by chromatography over silica gel (50 g.) andelution with ether gave 1.3 g. (26%) of the base(--)-3-phenoxy-N-[2-(2-furyl)ethyl])morphinan. For analysis, a sample ofthis compound was distilled, b.p. 145°-150° (0.1 mmHg), [α]_(D) ²⁵=-94.15° (c 1.06, MeOH).

To the above base, 1.2 g. (0.003 mol) in ether, a solution of 0.3 g. ofoxalic acid in ether was added. The crude oxalate was recrystallizedtwice from ethanol to give 1.0 g. (68%) of(--)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan oxalate, m.p. 195°-197°(d), [α]_(D) ²⁵ =-64.52° (c 1.03, MeOH).

EXAMPLE 26 (--)-3-Phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan

To a mixture of 4.0 g (0.012 mol) of (--)-3-phenoxymorphinan, 2.5 g. oftriethylamine and 15 ml. of methylene chloride was added dropwise asolution of 3.3 g. of 2-thienyl acetyl chloride in 15 ml. of methylenechloride. After the mixture had been refluxed for 15 hours, it wascooled to room temperature, diluted with methylene chloride and washedsuccessively with water, 4 N hydrochloric acid, 5 N sodium hydroxide andwater. The organic phase was dried and the solvent was evaporated togive 5.5 g. (100%) of the crude base(--)-3-phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan. For analysis, asample of this compound was distilled. b.p. 235°-240° (0.05 mmHg),[α]_(D) ²⁵ =-134.17° (c 1.03, MeOH).

EXAMPLE 27 (--)-3-Phenoxy-N-[2-(2-thineyl)ethyl]morphinan

To a suspension of 0.8 g of lithium aluminum hydride in 40 ml. ofanhydrous tetrahydrofuran was added dropwise 6.2 g. (0.014 mol) of(--)-3-phenoxy-N-[2-thienylmethyl)carbonyl]morphinan in 40 ml. ofanhydrous tetrahydrofuran. After the mixture had been refluxed undernitrogen for 3 hours, it was cooled to room temperature and water wasadded dropwise. The resulting suspension was filtered and the filtratewas concentrated. The residue was dissolved in ether and the etherealsolution was extracted with 4 N hydrochloric acid. The aqueous phase wasbasified with 10 N sodium hydroxide and extracted with ether. Theorganic phase was dried and the solvent was removed in vacuo to give 3.3g. (55%) of crude base(--)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinan.For analysis, a sample of this compound was distilled, b.p. 150° (0.05mmHg), [α]_(D) ²⁵ =-96.45° (c 1.23, MeOH).

The above base, 3.0 g. (0.007 mol) in ether was treated with sulfuricacid. The crude sulfate was recrystallized from methanol-ether to give1.8 g. (49%) of pure (--)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinansulfate, m.p. 135°-138°, [α]_(D) ²⁵ =-67.28° (c 1.00, MeOH).

EXAMPLE 28 (--)-3-(m-Fluoro)phenoxy-N-methylmorphinan

A mixture of 3.0 g. (0.011 mol) of (--)-3-hydroxy-N-methylmorphinan, 50ml. of freshly distilled pyridine, 2.2 g. of 3-bromofluorobenzene, 2.4g. of potassium carbonate and 3.0 g. of copper (granular) were heated ina stainless steel container at 120° for 8 days. After cooling, thecontainer was opened and the mixture was filtered. The filtrate wasconcentrated under reduced pressure and the residue was partitionedbetween ether and 10 N sodium hydroxide. The ether solution was washedwith water and dried. Removal of the solvent in vacuo gave a darkresidue which was distilled, b.p. 131°-140° (0.15 mmHg) to afford 0.5 g.(13%) of the base (--)-3-(m-fluoro)phenoxy-N-methylmorphinan, [α]_(D) ²⁵=-56.79° (c 1.04, MeOH).

To the above base, 0.4 g. (0.001 mol) in 2 ml. of acetone, a solution of0.2 g. of d-tartaric acid in 10 ml. of acetone was added. The crudetartrate was recrystallized from acetone to give 0.41 g. (71%) of(--)-3-(m-fluoro)phenoxy-N-methylmorphinan d-tartrate hemihydrate, m.p.121°-123°, [α]_(D) ²⁵ =-18.61° (c 1.03, MeOH).

EXAMPLE 29 (--)-3-(o-Methoxy)phenoxy-N-cyclopropylmethylmorphinan

To a solution of 1.7 g. (0.005 mol) of(--)-3-(o-methoxy)phenoxy-N-methylmorphinan in 25 ml. of toluene, 2.5 g.of cyclopropane carboxylic acid chloride in 15 ml. of toluene was addeddropwise under nitrogen at room temperature. The reaction mixture wasrefluxed for 13 days and the solvent was removed in vacuo. The residuewas partitioned between ether (500 ml.) and 4 N hydrochloric acid (200ml.). The ethereal solution was washed with dilute ammonium hydroxidethen with water and dried. Removal of the solvent gave 1.4 g. (71%) ofthe crude base(--)-3-(o-methoxy)-phenoxy-N-cyclopropylcarbonylmorphinan, which wasreduced without further purification.

To a suspension of 0.2 g. of lithium aluminum hydride in 20 ml. ofanhydrous tetrahydrofuran was added dropwise 1.0 g. (0.002 mol) of(--)-3-(o-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan in 10 ml. ofanhydrous tetrahydrofuran. After the mixture had been refluxed undernitrogen for 15 hours, it was cooled to room temperature and water wasadded dropwise. The resulting suspension was filtered and the filtratewas concentrated. The residue was partitioned between ether and 4 Nhydrochloric acid. The aqueous solution was basified with 10 N sodiumhydroxide and extracted with ether. The ethereal solution was washedwith water and dried. Removal of the solvent in vacuo gave 0.7 g. (725)of crude base (--)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinan.For analysis, a sample of this compound was distilled, b.p. 210°-220°(0.1 mmHg), [α]_(D) ²⁵ =-57.34° (c 0.52, MeOH).

The above base, 0.5 g. (0.001 mol) on treatment withhydrogen chloride(anhydrous) in ethyl acetate afforded the crude hydrochloride, whichafter crystallization from ethanol-ether gave 0.363 g. (67%) of(--)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride,m.p. 226°-227° (d), [α]_(D) ²⁵ =-71.18° (c 1.00, MeOH).

EXAMPLE 30 (--)-3-(p-Methoxy)phenoxy-N-cyclopropylmethylmorphinan

To a solution of 1.9 g. (0.005 mol) of(--)-3-(p-methoxy)phenoxy-N-methylmorphinan in 25 ml. of toluene, 2.9 g.of cyclopropane carboxylic acid chloride in 12 ml. of toluene was addeddropwise under nitrogen at room temperature. The reaction mixture wasstirred at reflux temperature for 13 days and the solvent was removedunder reduced pressure. The residue was partitioned between ether and 4N hydrochloric acid. The ethereal solution was washed with diluteammonium hydroxide, then water and dried. Removal of the solvent gave anoily residue which was distilled to give 1.2 g. (56%) of(--)-3-(p-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan, b.p. 170°(0.05 mmHg). This compound was used for the reaction without furtherpurification.

To a suspension of 0.4 g. of lithium aluminum hydride in 20 ml. ofanhydrous tetrahydrofuran was added dropwise 2.2 g (0.005 mol) of(--)-3-(p-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan in 10 ml. ofanhydrous tetrahydrofuran. After the mixture had been refluxed undernitrogen for 15 hours, it was cooled to room temperature and water wasadded dropwise. The resulting suspension was filtered and the filtratewas concentrated. The residue was partitioned between ether and 4 Nhydrochloric acid. The aqueous solution was made basic with 10 N sodiumhydroxide and extracted with ether. The etheral solution was washed withwater and dried. Removal of the solvent in vacuo gave 1.75 g. (825) ofthe crude base (--)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinan.For analysis, a sample of this compound was distilled, b.p. 215°-220°(0.25 mmHg), [α]_(D) ²⁵ =-77.78° (c 0.45, MeOH).

The above base, 1.5 g. (0.004 mol) on treatment with hydrogen chloride(anhydrous) in ethyl acetate afforded the crude hydrochloride.Recrystallization from ethanol-ether gave 1.27 g. (795) of(--)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride,m.p. 204°-206°, [α]_(D) ²⁵ =-60.50° (c 0.99, MeOH).

EXAMPLE 31

Tablet was formulated as follows:

    ______________________________________                                        Item   Ingredient             mg/tablet                                       ______________________________________                                        1.     (-)-3-phenoxy-N-methyl morphinan                                                                     5.0                                             2.     Lactose                99.0                                            3.     Pregelatinized starch  10.0                                            4.     Corn Starch            15.0                                            5.     Modified Starch        10.0                                            6.     Magnesium stearate     1.0                                                    Weight of tablet       140 mg                                          ______________________________________                                    

Procedure

1. Mix items 1, 2, 3, 4 and 5 in a suitable mixer, granulate with water.Dry over night in an oven. Mill through a Fitzpatrick mill.

2. Mix with item 6 and compress on a suitable press.

EXAMPLE 32

A tablet was formulated as follows:

    ______________________________________                                        Item     Ingredient          mg/tablet                                        ______________________________________                                        1.       (-)-3-phenoxy-N-methyl-                                                       morphinan           10.0                                             2.       Lactose anhydrous   103.0                                            3.       Avicel              45.0                                             4.       Modified starch     10.0                                             5.       Corn starch         30.0                                             6.       Magnesium stearate  2.0                                                       Weight of tablet    200 mg                                           ______________________________________                                    

Procedure

1. Mix items 1, 2, 3, 4 and 5 in a suitable mixer for 10 to 15 minutes.

1. Add magnesium stearate (item 6) as a premix and mix for 4 minutes.Compress on a suitable press.

EXAMPLE 33

A capsule Formulation

    ______________________________________                                        Item     Ingredient          mg/capsule                                       ______________________________________                                        1.       (-)-3-phenoxy-N-methyl-                                                       morphinan           10.0                                             2.       Lactose             218.0                                            3.       Corn Starch         50.0                                             4.       Magnesium stearate  2.0                                              5.       Talc                10.0                                                      Fill weight of capsule                                                                            220 mg                                           ______________________________________                                    

Procedure

1. Mix items 1, 2 and 3 in a suitable mixer. Mill through suitable mill.

2. Mix with items 4 and 5 and fill on capsule machine.

EXAMPLE 34

A capsule was formulated as follows:

    ______________________________________                                        Item Ingredient              mg/capsule                                       ______________________________________                                        1.   (-)-3-(p-methoxy)phenoxy-N-methyl-                                                                    25.0                                                  morphinan                                                                2.   Lactose                 257.0                                            3.   Corn Starch             70.0                                             4.   Magnesium stearate      3.0                                              5.   Talc                    15.0                                                  Fill weight of capsule  370 mg.                                          ______________________________________                                    

Procedure:

1. Mix items 1, 2 and 3 in a suitable mixer. Mill through suitable mill.

2. Mix with items 4 and 5 and fill on capsule machine.

EXAMPLE 35

A capsule was formulated in the manner of Example 34 except the activeingredient was (--)-(p-methyl)phenoxy-N-methylmorphinan.

EXAMPLE 36

A tablet was formulated (Wet Granulation) as follows

    ______________________________________                                        Item     Ingredients         mg/tablet                                        ______________________________________                                        1.       (-)-3-(p-methoxy)phenoxy-                                                     N-methylmorphinan   0.5                                              2.       Lactose             186.5                                            3.       Modified starch     35                                               4.       Pregelatinized starch                                                5.       Distilled water qs  --                                               6.       Magnesium Stearate  4                                                         Weight of tablet    250 mg                                           ______________________________________                                    

Procedure:

1. Mix items 1-4 in a suitable mixer.

2. Granulate with sufficient distilled water to proper consistency.Mill.

3. Dry in a suitable oven.

4. Mill and mix with magnesium stearate for 3 minutes.

5. Compress on a suitable press equipped with appropriate punches.

EXAMPLE 37

A tablet (Wet granulation) was formulated as follows:

    ______________________________________                                        Item  Ingredients             mg/tablet                                       ______________________________________                                        1.    (-)-3-pentafluorophenoxy-N-methyl-                                            morphinan               2.0                                             2.    Lactose                 253.0                                           3.    Modified starch         55                                              4.    Pregelatinized starch   35                                              5.    Distilled water qs      --                                              6.    Magnesium Stearate      5                                                     Weight of tablet        350 mg                                          ______________________________________                                    

Procedure:

1. Mix Items 1-4 in a suitable mixer.

2. Granulate with sufficient distilled water to proper considtency.Mill.

3. Dry in a suitable oven.

4. Mill and mix with magnesium stearate for 3 minutes.

5. Compress on a suitable press equipped with appropriate punches.

I claim:
 1. A compound of the formula ##STR17## wherein R is halo, loweralkyl, lower alkoxy, hydroxy, nitro or hydrogen; R₁ is hydrogen, loweralkenyl containing from 2 to 7 carbon atoms, --CH₂ --(CH₂)_(p) R₂, and##STR18## R₂ is phenyl, cyclo-lower alkyl containing from 3 to 6 carbonatoms, or a 5 or 6 membered heteroaromatic ring containing a hetero atomselected from the group consisting of oxygen, nitrogen and sulfur; p isan integer from 0 to 3; and n is an integer from 1 to 5; and the loweralkoxy and lower alkyl substituents contain from 1 to 7 carbon atoms andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein R₁ is lower alkyl.
 3. The compound of claim 2 wherein saidcompound is (--)-3-phenoxy-N-methylmorphinan.
 4. The compound of claim 2wherein R is halo.
 5. The compound of claim 4 wherein said compound is(--)-3-pentafluorophenoxy-N-methylmorphinan.
 6. The compound of claim 4wherein said compound is(--)-3-(p-fluoro)phenoxy-N-methylmorphinan. 7.The compound of claim 2 wherein R is nitro.
 8. The compound of claim 7wherein said compound is (--)-3-(o-nitro)-phenoxy-N-methyl-morphinan. 9.The compound of claim 2 wherein R is hydroxy.
 10. The compound of claim9 wherein said compound is (--)-3-(p-hydroxy)phenoxy-N-methylmorphinan.11. The compound of claim 2 wherein R is lower alkoxy.
 12. The compoundof claim 11 wherein said compound is(--)-3-(o-methoxy)phenoxy-N-methylmorphinan.
 13. The compound of claim 1wherein R₁ is --CH₂ --(CH₂)_(p) --R₂.
 14. The compound of claim 13wherein said compound is (--)-3phenoxy-N-cyclopropylmethylmorphinan. 15.The compound of claim 13 wherein R₁ is ##STR19##
 16. The compound ofclaim 13 wherein said compound is(--)-3-phenoxy17-cyclopropylcarbonylmorphinan.
 17. A compound of theformula ##STR20## wherein R is halo, nitro, lower alkyl, lower alkoxy,hydroxy or hydrogen and n is an integer from 1 to
 5. 18. The compound ofclaim 17 wherein said compound is(--)-3-phenoxyN-trichlorocarbethoxymorphinan.